The results from currently available studies either in-vitro, animal, human (observational) on the link between pioglitazone and bladder cancer are not consistent. Whether the positive link in patients using pioglitazone in some studies could be due to the drug per se, or due to the underlying disease of diabetes, the interactions with other concomitant drugs, the inherent flaws associated with study designs and statistical analyses, or the different ethnicities between studies, are worthy of discussion. Diabetes per se may increase the risk of cancer, probably via the activation of the Ras/Raf mitogen-activated protein kinase pathway in association with a reduction of the expression of epidermal growth factor receptor. In fact, epidemiologic studies also suggest an increased risk of bladder cancer in diabetic patients, independent of the commonly used oral anti-diabetic agents or insulin.